In a typical clinical setting, radiation therapy and/or chemotherapy treatments are administered to the majority (>90%) of cancer patients. Therefore, along with surgery, radiation therapy and chemotherapy represent two of the three main modalities employed for cancer treatment. However, the therapeutic outcomes are still far from ideal for many types of tumors. The main problem associated with radiotherapy is the recurrence of tumors and/or the development of metastases at distant locations. For chemotherapy, the problem is the development of resistance. Often, both radiotherapy and chemotherapy are associated with severe side effects. In both cases, new methods and compositions that can sensitize tumors to current treatments are highly desirable. Ideally, these methods and compositions should decrease local recurrences in patients treated with radiotherapy and/or should increase the efficacy of chemotherapeutic agents systemically. In addition, they should not have severe side effects.
Methionine adenosyltransferase (MAT) is a key enzyme required for every living cell. MAT II, an isozyme of MAT, is found in all human tissues and it is made of two nonidentical subunits that are called alpha (α2) and beta (β). MAT II β is the regulatory subunit, which regulates MAT II activity.
MAT, including MAT II, is responsible for the synthesis of one of the most important molecules in living organisms, called S-adenosylmethionine (SAM, or AdoMet). It has been shown that in certain types of cancerous cells require abnormally high levels of SAM. Therefore, MAT has been studied for years as a possible target for chemotherapy. Many scientists tried to develop inhibitors of this enzyme but most chemical inhibitors are highly toxic or lack specificity. Further, the synthesis of these chemical inhibitors in amounts that would be sufficient for treatment is costly.
What are needed, then, are new strategies and compositions for treating tumors and/or cancers via inhibition of MAT II activity that minimizes toxicity and/or improves specificity. The presently disclosed subject matter addresses this and other needs in the art.